Ophthalmic compositions and process of using

ABSTRACT

An ophthalmic composition and process for treating blepharitis employing the composition of 0.5-10% of available nonionic surfactant in water to emulsify and remove lipids from the corneal surface.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. patent applicationSer. No. 08/376,386, filed Jan. 23, 1995, now abandoned.

FIELD OF THE INVENTION

This invention relates to formulations suitable for alleviating theeffects of blepharitis and relieving or preventing the discomfortingcondition of "dry eye."

BACKGROUND OF THE INVENTION

Blepharitis is an abnormal condition wherein the tears produced containan excess of lipids (the oily ingredient in natural tears) and, in somecases, contain an irritating oil as well. As explained hereinafter, thisoil ingredient serves to prevent evaporation of the aqueous layer thatwets the corneal epithelium of the eye and helps spread the aqueouslayer over the normally aqueous-resistant cornea during a blink. Ifexcess oil is present, the lipid layer will tend to adhere to the corneaitself. If the eye is unable to clear this oil from the surface of thecornea, a "dry" area occurs on the cornea since the aqueous layer isunable to hydrate this area.

"Dry eye" can also occur because of a diminution of the quantity oftears produced and distributed through the lachrymal ducts, as well asthe previously described decrease in the stability of the tear filmproduced. "Dry eye" acts to decrease visual acuity; produces discomfort;and eventually, if allowed to remain untreated and uncorrected, mayresult in permanent damage with degradation of the exposed oculartissues, a complete breakdown of corneal tissue necessitating, in theextreme, corneal transplants.

Various compositions for treating "dry eye" have been proposed and putinto use over the years. For example, the treatments employed by ancientGreek physicians for this condition dominated medical practicethroughout the Middle Ages and into the nineteenth century. Theselection of components for ancient collyria, or for any of the eyetreatment preparations of the time, suggests either an instinctive orempirical knowledge of the composition of tears and tear films. Eggwhites, very rich in albumen (a major tear protein), and goose fat, alipid admixture, which, like meibomian lipids, becomes fluid attemperatures approximating normal body temperatures, have been used.

Use has also been made of substances which serve to induce a measure ofirritation, presumably to induce reflex tearing. Such substances asalcohols, acetic acid values of vinegar, onion fermentates and the likehave been utilized in this approach. Obviously, such methods are lessthan totally acceptable.

Other solutions offered for the alleviation of "dry eye" in more recentyears, i.e., during the 19th and early 20th century, have includedaqueous solutions of common table salt, glycerol, various oils andisotonic solutions of various salts, known as Ringer's and Locke'ssolutions.

Approximately forty years ago, the employment of aqueous solutions ofinert, substituted cellulose ethers, such as methyl cellulose, wasproposed, and such formulations are currently in use. Other substitutedcellulose ethers, such as hydroxyethyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose, have been subsequently utilizedas polymeric components in artificial tear formulations. Each of thesepolymeric materials imparts high viscosity to the tear formulations,even when employed in relatively low concentrations. It has been thisimpartation of high viscosity to the formulations which is believed toprolong retention time of the tear substitutes in the fornices and overthe preocular surface.

Recently, in U.S. Pat. No. 4,421,748 to Trager et al, a sterilehypotonic solution of 1-20 percent lecithin, preferably lecithinsulfate, and 0.1-20 percent of a cellulose-containingviscosity-adjusting agent, preferably hydroxyethyl cellulose, has beendisclosed as an artificial tear formulation. Such compositions possesssurface tensions approximating those of natural tears; and, if not,Trager et al. recommended the addition of 2-10 percent weight or volumeof a nonionic surfactant such as polyoxyalkylene oleic ester ofasorbitol anhydride to control surface tension of the artificial tearformulation.

It is an object of this invention to prevent "dry eye," or, if "dry eye"has occurred, to provide an improved formulation that quickly thereafterovercomes "dry eye" and permits the natural tears to operate in themanner that nature intended. It is a further object to avoid the use ofan oil to overcome "dry eye" since adding an oil, other than the amountof oil in a natural tear, tends to overcome "dry eye" only temporarily.Other objects will be apparent hereinafter.

SUMMARY OF THE INVENTION

The objects are accomplished by treating the eye with an aqueouscomposition containing an effective amount of a nonionic surfactant.Applicant has found that an effective amount of surfactant may compriseanywhere from 0.5 percent by weight and volume to about 10 percent byweight and volume (hereinafter %), preferably about 1-5%, of activesurfactant (not combined with oil) in the composition.

However, it should be noted that the use of any oil in the compositionwill reduce the effectiveness of the surfactant. The reason is that asubstantial percentage of the surfactant tends to serve as a vehicle fordissolving or forming an emulsion of the oil with the aqueous layer onthe cornea, thus reducing the ability of the aqueous layer to "wash" orhydrate the corneal surface. Thus, if any oil is used in thecomposition, then additional surfactant will be required to provide theeffective amount of 0.5-10%, preferably 1-5%, of available activenonionic surfactant.

THEORY AND DETAILS OF THE INVENTION

Eighty percent of patients with red irritated eyes have blepharitis. (Infact, on slit lamp examination, approximately 70% to 80% of thepopulation has abnormal meibomian glands and other signs ofblepharitis). They try artificial tears (or are given artificial tearpreparations to try by their eye specialist) and only use them brieflywith minimal success.

The success is minimal based on the following reasoning. Tears arecomposed of three layers, aqueous, mucin and lipid layers. The mucinlayer adheres to the corneal surface, which surface would repel waterwithout the mucin in place. The aqueous layer then provides wetting ofthe corneal epithelium by adhering or spreading over the mucin. Theouter lipid or oily layer prevents evaporation of the aqueous layer(without the lipid layer, tears would evaporate 10 to 20 times faster)and helps spread the aqueous layer during a blink. When the lipid layeradheres to the mucin layer, or to the cornea itself, rapid tear breakupoccurs. If the eye is unable to clear this oil off the surface, a dryarea occurs on the cornea as the aqueous material cannot hydrate it.

This is similar to oil in a frying pan. Simply running water over theoil does not remove it and the oil and the dry spot (the oil repels thewater) remains. In order to remove the oil, you have to wipe it off witha cloth or use a chemical (soap) to remove it.

When patients have blepharitis, they have an excess of oil; and, in somecases, an irritating oil rather than a soothing oil is produced. Theexcess oil thickens the lipid layer, adheres to the cornea in certainareas, and creates dry spots as the aqueous composition is preventedfrom getting to the corneal surface. The patient then notes that his eyeis red; his vision, blurry; and the eye starts to burn. It may thenstart to tear as the eye itself attempts to clear the oil from thesurface. If the patient rubs the eye, more oil is expressed from the oilglands and the symptoms get worse. Some of the proteins in the aqueouslayer may have surface-active properties and, thus, eventually may clearaway the oil. In general, however, since you cannot wipe the oil fromthe cornea with a cloth, and water alone will not wash it away, clearingthe eye becomes a very slow process.

However, with the composition of this invention, the problem is solvedquickly and more than temporarily. The invented composition acts todissolve away the excess lipid in the same manner as soap removes theoil or grease from the oil-covered frying pan. The action is quiteprompt and by restoring the smoothness of the tear film (eliminating thedepression of the tear film over the dry spot), blurring is eliminatedand vision is sharpened. The surface of the cornea simply gives itsshape to the tear film. As noted above, if the tear film is irregular inany way, some impairment of vision is bound to occur.

To summarize the theory of the invented solution to the problem:

Tears are composed of three (3) basic ingredients:

1. Mucin, a substance that tends to adhere to the corneal surface of theeye;

2. Water, which normally is repelled by the corneal surface, but tendsto adhere to and spread within the mucin layer; and

3. a lipid e.g., body-produced lecithin and/or similar oil, which tendsto cover the water-filled mucin layer, and thus reduce the evaporationrate of the aqueous system by anywhere from ten to twenty fold; and (asan oil) helps to lubricate the eye and, thus, permit the aqueous systemto spread over the corneal surface during a blink of the eye.

However, if the eye is unable to periodically clear the lipid oil fromthe corneal surface, the lipid oil layer will actually adhere to themucin layer or to the corneal surface itself. The aqueous layer thencannot penetrate sufficiently to form the aqueous system to hydrate theentire area of the cornea. The result is "dry eye" with accompanyingdiscomfort in at least one irritating dry area. As stated previously,the eye becomes red; the vision, blurry; and the eye starts to burn.Rubbing the eye causes the release of more oil from the individual's oilglands; and the symptoms become worse.

The use of artificial tear compositions of the prior art at this pointproduces temporary relief. The artificial tear compositions tend tomerely add aqueous solutions. However, the basic problem of allowing theindividual's aqueous system to adhere to the mucin layer and, then coverthe corneal surface does not occur if the interference by the lipid oiladherent to the oil-preferring corneal surface is not resolved.

This invention, the use of an aqueous composition containing 0.5% to 10%of an active, available nonionic surfactant overcomes "dry eye" for muchlonger than merely the temporary basis of the prior art compositions.However, it should be understood that the compositions of the inventionmay also contain a viscosity-adjusting agent, (hydroxypropyl methylcellulose, or the like) a tonicity adjusting agent (sodium and/orpotassium chloride, anhydrous dextrose, etc.), a sequestering agent(sodium citrate or the like), a preservative agent (benzalkoniumchloride, sodium ethyl mercuriothiosalicylate or the like), a bufferingagent (an alkali meal phosphate); etc. The invented compositions shouldnot contain any ingredient that will detract sufficiently to lower theactivity of the critical nonionic surfactant below thepreviously-mentioned effective percentages. Thus, the active nonionicsurfactant may be used along with the commercial tear aid compositionsof the prior art provided that these commercial compositions do notcontain amounts of interfering substances that will tie up the nonionicsurfactant to below the aforementioned effective amounts.

The interfering substances usually comprise oil substances (lecithin orother lipids) which attach to the surfactant chemically and then formemulsions with the aqueous system. As explained hereinafter, thissolubilizing or emulsion-forming activity reduces the available surfaceactivity of the surfactant. It is also important to refrain fromincluding in the composition of this invention ionic materials, e.g.,ionic polysaccharides, which form thermo-irreversible gels with thenonionic surfactant.

The preferred nonionic surfactants for use in the aqueous composition ofthis invention are block copolymers of ethylene oxide and propyleneoxide manufactured by the BASF Company as "PLURONICS" and "Poloxamers."

The unique structure of these copolymers allow a novel approach in thedesign of surface-active agents. While other nonionic surfactants have afixed hydrophobe and can effect changes in surfactant function only byaltering the hydrophile, these ethylene oxide/propylene oxide blockcopolymers allow alteration of both the hydrophobic and hydrophilicentities. In addition, heteric structures can be introduced internallyor at the end of the molecule, and the total molecular weight of theagent can be varied.

In synthesizing these surfactants, the usual first step is to create ahydrophobe of desired molecular weight. Specifically, propylene oxide isadded to the two hydroxyl groups of propylene glycol. Ethylene oxide isthen added to sandwich the hydrophobe between hydrophilic groups, thelatter being controlled by length to constitute from 10% to 80% (byweight) of the final molecule.

The structure of these surfactants is shown below: ##STR1##

For the purpose of removing the lipid oil from the corneal surface orfrom the mucin layer, it is necessary to form an emulsion. To form anemulsion of the oil in water, a surfactant or emulsifier that is moresoluble in water than in oil will usually be used. Hence, apredominantly hydrophilic emulsifier, e.g., PLURONIC F68, will be used.To form an emulsion of water in oil, a surfactant that is predominantlyhydrophobic or lipophilic, e.g., PLURONIC L44, will be used. For thepresent invention, both types of surfactants have been found useful.

In the following table, the properties of the PLURONIC surfactants thatI have used successfully in this invention are presented:

                  TABLE I    ______________________________________                            Melt        Surface          Average           Point                                 Viscosity                                        Tension    Product          Molecular Wt.                     Form   °C.                                 cps    dynes/cm                                               HLB    ______________________________________    L44   2200       liquid 16   440    45     12-18    F68   8400       solid  52   1000   50     >24    F87   7700       solid  49   700    44     >24    F127  12600      solid  56   3100   41     18-23    L64   2900       liquid 16   850    43     12-18    ______________________________________

Thus, the block copolymers of ethylene oxide and propylene oxide that Ihave found useful in the compositions of the invention may behydrophilic solids or hydrophobic liquids; have a molecular weight ofabout 2000-13000; pour points of 16°-56° C.; viscosities of about400-3500 cps; surface tensions of about 40-50 dynes/cm; and HLB valuesof 12 to greater than 24.

Other nonionic surfactants useful in this invention include thepolyoxyalkylene oleic esters of sorbitol anhydrides, e.g., polysorbate80, disodium oleamide polyethylene glycol--2 sulfosuccinate;cocoamphocarboxyl glycinate, and any of those listed in Table I on pages253-255 of Journal of Society Cosmetic Chemists, Vol. 5(4), 1054, in thearticle entitled "Calculation of HLB Values in Non-Ionic Surfactants" byW. C. Griffin, having HLB values from 12 to greater than 24. ThisGriffin article is incorporated herein by reference.

In addition, the formulations may contain up to about 1% of one or moreviscosity-adjusting agents; up to about 1% of one or more tonicityadjusting agents; usually about 0.3% of one or more buffering agents;and less than 0.1% of a preservative agent.

Use of the composition is conveniently performed by instilling thecomposition in liquid form drop-wise, into the eye or eyes of thepatient. Since the eye cannot hold a full drop from a dispensing bottle,some solution will necessarily spill onto the eye lids and lashes, thesources of the excess oil in blepharitis patients. By having a liquidwhich is not strong enough to disrupt the tear film to the point ofdiscomfort, but able to remove the excess oil from the tear film, theeye lids and lashes, the patient receives relief from the burning anditching of blepharitis. Prophylactic treatment for further irritationlater in the day may be simultaneously performed. Thus, symptomaticrelief, as well as treatment of the underlying problem, is accomplishedby the use of the composition of the invention.

In summary, the use of the composition of this invention serves as atreatment for blepharitis, relieves red irritated eyes, improves visualblur caused by the presence of excess oil and thins excess oil from theocular surface. It should be noted, however that temporary blurring ofvision can occur if the drop is used and the tear film is at a normalthickness, with respect to lipids; or irritation of the eye could occurif the drop is used too often and too much lipid has been removed.

The invention will be more clearly understood by referring to thefollowing examples:

EXAMPLE 1

The following six (6) formulations of nonionic surfactants in purifiedor sterile water but also containing 0.055% monobasic sodium phosphate,0.227% anhydrous dibasic sodium phosphate, 0.6% sodium chloride, 0.075%potassium chloride, 0.003% anhydrous dextrose, 0.1% Dextran 70, 0.8%hydroxypropyl methyl chloride, 0.01% benzalkonium chloride wereprepared:

A. 1% "Poloxamer" 188 (PLURONIC F68)

B. 4% "Poloxamer" 185 (PLURONIC L64)

C. 1% Disodium Oleomides

D. 4% Cocoamphocarboxyl

E. 0.1% "Poloxamer" 188 (PLURONIC F68) 0.4% "Poloxamer" 185 (PLURONICL64) 0.2% Disodium Oleomides PEC-2 Sulfosuccinate 0.4%Cocoamphocarboxyl-glycinate

F. 1 % Polysorbate 80

When instilled into the eye of an adult, in the form of drops, "dry eye"was alleviated within 5 to 10 minutes with all formulations:

Formulation A produced no burning sensation.

Formulation B produced no stinging, but some blurring. However, the eyesfelt moist and comfortable two (2) hours later.

Formulation C produced a stinging sensation upon being instilled butquite comfortable 12 hours later.

Formulation D produced some initial stinging; vision cleared but somestinging persisted.

Formulation E produced some initial stinging but vision cleared.

Formulation F produced no stinging; blurred vision for 1-3 minutes butvision cleared afterward.

It is believed that the effect on vision (blurred or clear) dependedupon the initial oil concentration on the ocular surface.

EXAMPLE II

In further testing, the preferred "Poloxamer" or PLURONIC ethyleneoxide-propylene oxide block copolymers were used in amounts ranging from1 to 5% (by weight) with the following results:

G. "Poloxamer" 188, also known as PLURONIC F 68NF was used to provide acomfortable initial feeling and the eye felt comfortable for a longperiod of time afterwards;

H. "Poloxamer" 407, also known as PLURONIC F127 provided a comfortableinitial feeling which persisted for at least two hours;

I. "Poloxamer" 237, also known as PLURONIC F87NF provided a comfortableinitial feeling which lasted over one hour;

J. "Poloxamer" 124, also known as PLURONIC L 44N provided a comfortableinitial feeling with some initial blurring of contact lenses, whichblurring disappeared after about 15 minutes and where the experimenterexperienced a significant improvement after about one hour whichcomfortable feeling persisted thereafter.

What is claimed is:
 1. An aqueous composition to effect a significantimprovement for a significant period of time in the treatment ofblepharitis consisting essentially of greater than zero to about 1% ofat least one tonicity-adjusting agent, greater than zero to about 0.1%of a preservative agent, greater than zero about 0.3% of at least onebuffering agent, said ingredients being present in an amount of from0.07% to 1.4% by weight, said per cent being based upon weight pervolume and an amount of a nonionic surfactant comprising a blockcopolymer of 20-80% ethylene oxide and 80-20% propylene oxide having amolecular weight of about 2000-13000, a viscosity of about 400-3500centipoises, a surface tension of about 40-50 dynes/centimeter and anHLB value of at least 12 in sterile water sufficient to provide 0.5-10%by weight of available nonionic surfactant.
 2. A process to effect asignificant improvement for a significant period of time in thetreatment of blepharitis comprising (1) contacting the surface of thecornea having lipids on its surface with an aqueous compositionconsisting essentially of: greater than zero to about 1% of at least oneviscosity-adjusting agent, greater than zero to about 0.1% of apreservative agent, greater than zero about 0.3% of at least onebuffering agent, said ingredients being present in an amount of from0.07 to 1.4% by weight, said per cent being based upon weight per volumean amount of a nonionic surfactant comprising a block copolymer of20-80% ethylene oxide and 80-20% propylene oxide having a molecularweight of about 2000-13000, a viscosity of about 400-3500 centipoises, asurface tension of about 40-50 dynes/centimeter and all HLB value of atleast 12 in sterile water sufficient to provide 0.5-10% by weight ofavailable nonionic surfactant to dissolve said lipids on said surface ofsaid cornea; (2) removing said composition containing dissolved lipids;and (3) permitting the mucin and aqueous layers of the natural tear tocontact the complete surface of the cornea.
 3. A process as in claim 2wherein said viscosity-adjusting agent is hydroxy propyl methylchloride.
 4. A process as in claim 2 wherein said tonicity-adjustingagent is selected from the group consisting of sodium chloride,potassium chloride and dextrose.
 5. A process as in claim 2 wherein saidpreservative agent is benzalkonium chloride.
 6. A process as in claim 2wherein said buffering agent is selected from the group consisting ofmonobasic sodium phosphate and anhydrous dibasic sodium phosphate.
 7. Aprocess as in claim 2 wherein the amount of said nonionic surfactant issufficient to provide about 1-5% of available nonionic surfactant.